1. Field of the Invention
The invention relates to the chemistry of biologically active compounds. More particularly to porphyrin and chlorin derivatives in combination with polymers that can be used as photosensitizers for a wide range of light irradiation treatments such as photodynamic therapy of cancer, infections and other diseases. The porphyrin and chlorin derivatives of the present invention may be attached to the polymer but may also be released upon certain triggers.
2. Invention Disclosure Statement
Photodynamic therapy (PDT) is one of the most promising techniques being explored for use in a variety of medical applications [1], [2] and particularly is a well-recognized treatment for the destruction of tumors [3]. Photodynamic therapy uses light and a photosensitizer (a dye) to achieve its desired medical effect. A large number of naturally occurring and synthetic dyes have been evaluated as potential photosensitizers for photodynamic therapy. Perhaps the most widely studied photosensitizers are the tetrapyrrolic macrocyclic compounds. Among them, especially porphyrins and chlorins have been tested for their PDT efficacy. Porphyrins are macrocyclic compounds with bridges of one carbon atom joining pyrroles to form a characteristic tetrapyrrole ring structure. There are many different classes of porphyrin derivatives including those containing dihydro-pyrrole units. Chlorins, as referred to in the present invention, are porphyrin derivatives containing one dihydro-pyrrole unit whereas bacteriochlorins are characterized by two dihydro-pyrrole units (in general in chlorins one double bond of the aromatic system in β-position is absent and in bacteriochlorins two opposite double bonds are absent compared to the porphyrin). As examples of tetrapyrrolic macrocyclic compounds used as photosensitizers, US Publication No. 2012/0,263,625A1 from Aicher et al. discloses glyco-substituted dihydroxy-chlorins for antibacterial PDT, U.S. Pat. No. 7,022,843B1 from MacAlpine et al. provides)β,β′-dihydroxy meso-substituted chlorins as photosensitizers, and U.S. Pat. No. 7,166,719B2 from Pandey et al. discloses tetrapyrrole compounds containing a fluorinated substituent where the compound is a chlorin or a bacteriochlorin for PDT diagnostic and therapeutic application.
There are several properties that an effective photosensitizer should accomplish. Among them, a desirable characteristic in order to efficiently destroy deep target tissues is a strong absorption at long wavelength. Many current photosensitizers are not efficient enough as they have low absorption in the red region of the spectrum. Chlorins have the advantage that they possess an intense absorption in the red and near-infrared region of the electromagnetic spectrum. As light of longer wavelength penetrates deeper into the tissue, it is thus possible to treat e.g. more expanded tumors, if the PDT is employed for tumor therapy. Chlorins possessing potential for PDT can either be derived from natural sources or from total synthesis. Another issue for PDT is the non-specific accumulation of the photosensitizer in undesired tissues (e.g. the skin) which leads to—in the case of skin accumulation—prolonged photosensitivity of the patient which is unpleasant for the patient and can lead to severe burns and scarring.
Thus, there is a need to enhance the effectiveness of prior art biologically active compounds used as photosensitizers in order to successfully perform a wide range of light irradiation treatments such as photodynamic therapy of cancer, infections and other diseases. Moreover, it is necessary to provide novel methods of preparation and improved photosensitizer formulations more potent than those available up to date.
Photosensitzers for anti-tumor PDT are highly lipophilic compounds with a low or no water solubility [4]. So, for the administration of photosensitizers suitable pharmaceutical formulations are needed. In this respect, International Publication No. WO2011071970 by Langer et al. discloses suitable photosensitizer formulations based on poly-lactic-co-glycolic-acid (PLGA) whereas International Publication No. WO2011071968 by Langer et al. discloses formulations based on human serum albumin (HSA) nanoparticles. International Publication No. WO2005023220 by Albrecht et al. discloses suitable liposomal formulations for the photosensitizers that are subject of the present invention. Possible oral formulations for such photosensitizers are described in International Publication No. WO2010129337 by Graefe et al. and in International Publication No. WO2010129340 by Farmer et al.
Nanoparticle formulations of photosensitizers for tumor treatment can benefit from the EPR effect (enhanced permeability and retention effect) of malign tissue where particles of a certain size can more easily leave the blood stream due to the specific structure of tumor tissue and where they are retained for longer periods due to the underdeveloped lymphatic system [5], [6]. In the art, a number of methods are described to connect photosensitizer molecules to macromolecular or nanoparticle carriers [7]. One example for possible carrier systems are polymers. International Publication No. WO2008130181A1 by Kwon et al. discloses polymers as carrier systems for pharmaceuticals. However, specifically for photosensitizers there is a need to release the photosensitizer molecule from the nanoparticle or the macromolecular carrier, given that the close proximity of the photosensitizer molecules to the carrier system changes their photophysical behavior and may lead to a suppression of the desired action, i.e. the generation of reactive oxygen species (ROS) on illumination.